Youth experiencing homelessness (YEH) are at high risk for HIV, with prevalence estimates as high as 13%, underscoring the need for targeted HIV prevention programs. YEH engage in more sexual risk behaviors than stably housed youth, yet underutilize existing HIV prevention programs and prevention care delivery, including low uptake of PrEP and nPEP. Nurse case management (NCM) enhanced with motivational interviewing (MI) strategies and behavioral feedback may increase engagement of youth to adopt and adhere to behavioral and biomedical HIV prevention methods. NCM is a proven public health approach that involves coordinated, individualized, comprehensive care delivered by a registered nurse that includes health assessment, care plan development, prevention education, and health and social service navigation and addresses the social determinants of health including behavioral, psychosocial, and situational factors to optimize HIV prevention in this high risk population. Guided by the Comprehensive Health Seeking and Coping Framework, we will conduct a randomized controlled trial of an enhanced NCM intervention, NCM4HIV, delivered to YEH 16-25 years old in collaboration with health and social service providers to assess the intervention?s effect on uptake of and adherence to HIV prevention strategies. NCM4HIV is an enhanced HIV prevention case management that provides direct HIV prevention services (PrEP, nPEP) and individualized HIV prevention planning using MI and behavior feedback technology. Aim 1: Determine whether the enhanced NCM intervention increases uptake of HIV prevention strategies (PrEP and nPEP uptake, HIV testing, STI screening and treatment, and condom use) when compared with usual care received by YEH (N=450; aged 16-25 years). Aim 2: Determine whether NCM4HIV improves mental health, substance use, and housing status when compared with control youth at baseline, immediate post and 3, 6, and 9 months. As an exploratory aim, we will determine whether whether health seeking, coping, HIV risk perception, PrEP/nPEP barriers and facilitators, and condom self- efficacy mediate the effect of the intervention on uptake of PrEP/nPEP and condom use. This early-stage and new-investigator initiated R01 is significant because it has the ability to improve uptake of HIV prevention strategies and reduce new HIV cases in a high-prevalence group. NCM4HIV is innovative because it uses nurses to directly deliver enhanced NCM and can be applied to improve any existing YEH HIV prevention program, making it a highly scalable and sustainable model that capitalizes on the ?come as you are? approach promoted by the National Healthcare for the Homeless Council (NHCHC). It aligns with the NIH HIV High Priority Research Areas for reducing HIV by identifying strategies to adopt, integrate, and scale up sustainable interventions in high HIV-prevalence and substance-using groups. If NCM4HIV is efficacious, we will work with NHCHC to scale it across the 300 programs and 3,300 homeless clinics that serve youth experiencing homelessness.